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DsbA-L ameliorates renal aging and renal fibrosis by maintaining mitochondrial homeostasis

Acta Pharmacologica Sinica volume 45, pages 777–789 (2024)Cite this article

Abstract

Renal fibrosis is the final pathological change in renal disease, and aging is closely related to renal fibrosis. Mitochondrial dysfunction has been reported to play an important role in aging, but the exact mechanism remains unclear. Disulfide-bond A oxidoreductase-like protein (DsbA-L) is mainly located in mitochondria and plays an important role in regulating mitochondrial function and endoplasmic reticulum (ER) stress. However, the role of DsbA-L in renal aging has not been reported. In this study, we showed a reduction in DsbA-L expression, the disruption of mitochondrial function and an increase in fibrosis in the kidneys of 12- and 24-month-old mice compared to young mice. Furthermore, the deterioration of mitochondrial dysfunction and fibrosis were observed in DsbA-L−/− mice with D-gal-induced accelerated aging. Transcriptome analysis revealed a decrease in Flt4 expression and inhibition of the PI3K-AKT signaling pathway in DsbA-L−/− mice compared to control mice. Accelerated renal aging could be alleviated by an AKT agonist (SC79) or a mitochondrial protector (MitoQ) in mice with D-gal-induced aging. In vitro, overexpression of DsbA-L in HK-2 cells restored the expression of Flt4, AKT pathway factors, SP1 and PGC-1α and alleviated mitochondrial damage and cell senescence. These beneficial effects were partially blocked by inhibiting Flt4. Finally, activating the AKT pathway or improving mitochondrial function with chemical reagents could alleviate cell senescence. Our results indicate that the DsbA-L/AKT/PGC-1α signaling pathway could be a therapeutic target for age-related renal fibrosis and is associated with mitochondrial dysfunction.

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Fig. 1: DsbA-L expression was downregulated, and cellular senescence was observed in aging kidneys.
Fig. 2: Disturbed mitochondrial homeostasis was observed in aging renal tissue.
Fig. 3: Aggravated cellular senescence and fibrosis levels in the kidneys of DsbA-L gene-deficient mice.
Fig. 4: Decreased Flt4 and inhibited AKT/SP1/PGC1α signaling were observed in the kidneys of DsbA-L-knockout mice.
Fig. 5: AKT agonists (SC79) and mitochondrial protectants (MitoQ) significantly ameliorated cellular senescence and fibrosis levels in the kidneys of aging mice.
Fig. 6: Overexpression of DsbA-L restored Flt4 expression and ameliorated mitochondrial function, cellular senescence, and fibrosis in D-gal-treated HK-2 cells.
Fig. 7: AKT agonists (SC79) and mitochondrial protectants (MitoQ) significantly ameliorated cellular senescence and fibrosis levels in D-gal-treated HK-2 cells.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by grants from the Natural Science Foundation of Hunan Province (2021JC0003).

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  1. These authors contributed equally: Ming Yang, Yan Liu

Authors and Affiliations

  1. Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China

    Ming Yang, Yan Liu, Shi-lu Luo, Chong-bin Liu, Na Jiang, Chen-rui Li, Hao Zhao, Ya-chun Han, Wei Chen, Li Li & Lin Sun

  2. Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, 410011, China

    Ming Yang, Yan Liu, Shi-lu Luo, Chong-bin Liu, Na Jiang, Chen-rui Li, Hao Zhao, Ya-chun Han, Wei Chen, Li Li & Lin Sun

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Contributions

MY and YL performed the experiments and wrote the manuscript. SLL, CBL, NJ, CRL, HZ, YCH, WC, and LL provided technical support for this study and participated in discussions about this study. MY and LS designed this study and edited this manuscript. LS is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All the authors have read and approved the final manuscript.

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Correspondence to Lin Sun.

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Yang, M., Liu, Y., Luo, Sl. et al. DsbA-L ameliorates renal aging and renal fibrosis by maintaining mitochondrial homeostasis. Acta Pharmacol Sin 45, 777–789 (2024). https://doi.org/10.1038/s41401-023-01216-1

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